The human IL-2 receptor and related cytokine receptor systems are being studied to clarify the T cell immune response in normal, neoplastic, and immunodeficient states. The current focus is on mechanisms of signal transduction. Following T-cell activation by antigen, the magnitude and duration of the T-cell immune response is determined by the amount of IL-2 produced, levels of receptors expressed, and time course of each event. The IL-2 receptor contains three chains, IL-2Ra, IL-2Rb, and gc. Dr. Leonard cloned IL-2Ra in 1984, his group discovered IL-2Rb in 1986, and reported in 1993 that mutation of the gc chain results in X-linked severe combined immunodeficiency (XSCID, which has a T-B+NK- phenotype) in humans, and in 1995 that mutations of the gc- associated kinase, Jak3, result in an autosomal recessive form of SCID indistinguishable from XSCID. The group reported in the past year that T-B+NK+ SCID results from mutations in the IL7R gene. Not only did this establish the basis for a novel form of SCID, but it also demonstrated that IL7R-dependent signaling is not required for B-cell development in humans, even though it is vital for this development in mice, underscoring a major difference in B-lineage development in humans and mice. It was also reported that IL-2 signaling required recruitment of phosphatidylinositol 3-kinase and that this is cooperatively done via the IL-2 receptor b chain and the IL-2Rb-associated kinase, Jak1. Using gc-knockout mice mated to Bcl-2 transgenic mice, it was also discovered that Bcl-2 is important for alpha-beta T-cell development and that its role differs depending on the TCR/MHC affinity. During the past year, significant advances were made regarding the establishment of a gene- therapeutic approach towards correcting the defect in gc-knockout mice. Interestingly, this correction could occur with human gc, indicating the ability of human gc to functional cooperate with murine cytokines and the other receptor components of these murine cytokines. Finally, the lab made additional progress in dissecting out the mechanism of action of two negative regulators of signaling, CIS (cytokine-inducible SH2 containing protein; also called CIS1) and JAB/SOCS1/SSI-1, which is related to CIS. Finally, IL-2-inducible genes are being identified and a novel method is being set up for the potential identification of novel proteins involved in IL-2 signaling. These studies help to clarify both positive and negative regulation of IL-2 signaling. - XSCID, IL-2, IL-2 receptor, IL-7R, Signaling, PI 3-kinase, Jak1, IL- 2Rb, gc